Cholesterol gallstone dissolution in bile - The Journal of Lipid ...

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Hile TABLE 4. Static disk method: stagnant (unstirred) dissolution of cholesterol monohydrate" (:holesterol Solubilized (mgidl) 1I:itial Disso- Time (Hr) lution Rate Diwdurion Kate ( ~ n m o.cnm". l (:onst;unt (k) Salt 1 2 4 6 8 \ = (1 \e
Fig. 13. Crystal habits, high- and low-angle X-ray powder diffraction patterns and unit cell crystallographic structures of anhydrous cholesterol (ChA) and cholesterol monohydrate (ChM). Reproduced from refs. 8.27. and 28 with kind permission of the copyright owners (Mac- Millan Publications and Lipid Research Inc.) and the authors. after, the solubilities of ‘ChA’ decreased to level off at values equivalent to equilibrium ChM solubilities and hence reflected a change in micellar solubility of cholesterol due to the conversion of ChA to ChM. Thus the attempt of the system to achieve equilibrium solubility of ChA (as in the disk experiments) is rapidly counteracted by a change in micelle solubility due to hydration of ChA + ChM and continuous nucleation in the presence of excess cholesterol. In the present studies, not only were equilibrium micellar solubilities of ChA (Table 1, Fig. 5) 1.2 to 2.2 (mean 1.53)-times greater than the micellar solubility of ChM, but dissolution rates were 2 to 3-fold faster. Based on our previous analysis of the molecular determinants of ChM solubility in bile salt micelles (33), we can con- clude that the monomeric aqueous solubility of ChA must be greater than ChM and hence would be a factor in accelerating the dissolution rates. However, the crystal lattice energy may also be important in the dissolution process since the micellar binding of cholesterol is the result of two coupled equilibria Chcrusta~ * Chmonomer * Chmleellar Eq‘ 6 As shown in Fig. 13, the ChM bilayer in the unit 266 Journal of Lipid Research Volume 22, 1981 cell is held together by strong H-bonding to an inter- linked lattice of H20 molecules, whereas in the unit cell of ChA only weak H-bonds between opposing OH groups of two cholesterol molecules are involved (27, 28). The prolonged (21-day) metastability of solubilized ChA in the UDC conjugates (Fig. 6) is most likely to be related to resistance to nucleation rather than hydration, since our results for CDC (Fig. 6) show that powdered ChA is hydrated in 2-6 days. This finding is paralleled by the extensive metastable solubility of the insoluble protonated form of UDC and GUDC when solubilized by their own micelles during potentiometric titration (9). As emphasized by Mufson et al. (30) and Carey and Small (10) earlier, the micellar solubility of cholesterol when dried from organic solvents (method of coprecipitation) is quite similar to the present ChA solubility results (Fig. 6B) since the cholesterol initially formed by this process is anhydrous. Hence, if sufficient time is not allowed for equilibration (hydration of ChA and nucleation and precipitation of excess ChM), falsely high values of “ChM” solubility will be obtained. For reasons outlined above, it is apparent that true equilibrium solubilities of ChM in UDC micelles can only Downloaded from www.jlr.org by guest, on June 9, 2013
Page 1 and 2: Cholesterol gallstone dissolution i
Page 3 and 4: A. STATIC DISC B. ROTATING DISC cho
Page 5 and 6: Fig. 3. Dissolution rate constants
Page 7 and 8: 0 l1 HWRS - 120 GCDC -90 TCDC -60 -
Page 9 and 10: a 7 A. ChM I 7 TCDC UDC DAYS L I Fi
Page 11: MINUTES Fig. 10. Influence of rotat
Page 15 and 16: hypothesis has recently been advanc
Page 17: 27. Craven, B. M. 1976. Crystal str

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